The present invention relates to novel 1H-imidazopyridine derivatives or salts thereof which have a potent inhibitory action against production of tumor necrotizing factor (TNF) or interleukin-1 (IL-1) and are useful as medicaments for preventive or therapeutic treatment of diseases of humans and animals in which a cytokine such as TNF, IL-1 is mediated, which include chronic inflammatory diseases (e.g., rheumatic arthritis, osteoarthritis, etc.), allergic rhinitis, atopic dermatitis, contact dermatitis, asthma, sepsis, septic shock, various autoimmune diseases [autoimmune hemic diseases (e.g., hemolytic anemia, anaplastic anemia, idiopathic thrombocythemia, etc.), autoimmune intestinal diseases (e.g., ulcerative colitis, Crohn""s disease, etc.), autoimmune corneitis (e.g., keratoconjunctivitis sicca, spring catarrh, etc.), endocrine ophthalmopathy, Graves disease, sarcoid granuloma, multiple sclerosis, systemic erythematodes, multiple chondritis, pachydermia, active chronic hepatitis, myasthenia gravis, psoriasis, interstitial pulmonary fibrosis and the like], diabetes, cancerous cachexia, HIV-infectious cachexia and the like.
Some compounds having 1H-imidazoquinoline structure are known which are analogous to the compounds of the present invention. Journal of Medicinal Chemistry, Vol. 11, p. 87 (1968) discloses 1-(2-piperidinoethyl)-1H-imidazo[4,5-c]-quinoline, Japanese Patent Unexamined Publication (KOKAI) No. Sho 60-123488/1985 discloses 1-isobutyl-1H-imidazo[4,5-c]quinoline-4-amine (general name: imiquimod) as a compound having an antiviral action, and Hungarian Patent Publication No. 34479 (Patent No. 190109) discloses 1-(2-diethylamino-ethyl)-1H-imidazo[4,5-c]quinoline as a compound having analgesic and anticonvulsant actions. However, 1H-imidazopyridine derivatives as those according to the present invention have never been known so far.
Moreover, the aforementioned imiquimod has been known to have an inducing action of a few kinds of cytokines such as interferon (IFN), TNF, IL-1 and the like, which is described in Journal of Interferon Research, Vol. 14, p. 81 (1994). However, 1H-imidazopyridine derivatives or 1H-imidazoquinoline derivatives having an inhibitory action against production of TNF or IL-1, which action is totally opposite to those taught by the aforementioned prior arts, have never been known so far.
An object of the present invention is to provide novel compounds which have excellent inhibitory actions against production of cytokines such as TNF and IL-1 and the like are useful as medicaments.
The inventors of the present invention made intensive studies to achieve the object. As a result, they found novel 1H-imidazopyrdine derivatives which have an excellent inhibitory action against production of TNF or IL-1 and achieved the present invention.
Tile present invention thus relates to novel 1H-imidazopyridine derivatives represented by the following general formula (I) or salts thereof: 
wherein R1 represents hydrogen atom, hydroxyl group, an alkyl group which may have one or more substituents, a cycloalkyl group which may be substituted, a styryl group which may be substituted, or an aryl group which may have one or more substituents; R2 represents hydrogen atom, an alkyl group, a halogen atom, hydroxyl group, an amino group which may have one or two substituents, a cyclic amino group which may be substituted, or a phenoxy group which may be substituted; ring A represents a homocyclic or heterocyclic ring which may be substituted with one or more alkyl groups, alkoxyl groups, or halogen atoms; R3 represents a saturated nitrogen-containing heterocyclic group which may be substituted; and m represents an integer of from 0 to 3; provided that, when R3 represents unsubstituted piperidino group, at least one of R1 and R2 is not hydrogen atom.
According to the second embodiment of the present invention, there are provided novel 1H-imidazopyridine derivatives represented by the following general formula (II) or salts thereof: 
wherein R1, R2, ring A and m have the same meanings as those defined above; R4 represents hydrogen atom, an alkyl group, benzyl group, triphenylmethyl group, an alkanoyl group which may be substituted, an alkoxycarbonyl group, benzyloxycarbonyl group, a thiocarbamoyl group which may be substituted, an alkanesulfonyl group, a benzenesulfonyl group which may be substituted, or amidino group; Y represents methylene group, oxygen atom, sulfur atom, nitrogen atom, a group represented by NH, or a single bond; and n represents an integer of from 0 to 2.
According to the third embodiment of the present invention, there are provided, among the compounds represented by the aforementioned general formulas (I) and (II), the compounds wherein ring A is a benzene ring or a thiophene ring, or the salts thereof.
According to another aspect, there is provided a medicament which comprises as an active ingredient the compound represented by the aforementioned general formula (I) or (II), or a pharmacologically acceptable salt thereof. The medicament is useful for preventive or therapeutic treatment of diseases of mammals including humans, in which a cytokine such as TNF, IL-1 is mediated, which include chronic inflammatory diseases (e.g., rheumatic arthritis, osteoarthritis, etc.), allergic rhinitis, atopic dermatitis, contact dermatitis, asthma, sepsis, septic shock, various autoimmune diseases [autoimmune hemic diseases (e.g., hemolytic anemia, anaplastic anemia, idiopathic thrombocythemia, etc.), autoimmune intestinal diseases (e.g., ulcerative colitis, Crohn""s disease, etc.), autoimmune corneitis (e.g., keratoconjunctivitis sicca, spring catarrh, etc.), endocrine ophthalmopathy, Graves disease, sarcoid granuloma, multiple sclerosis, systemic erythematodes, multiple chondritis, pachydermia, active chronic hepatitis, myasthenia gravis, psoriasis, interstitial pulmonary fibrosis and the like], diabetes, cancerous cachexia, HIV-infectious cachexia and the like.
According to a further aspect, there are provided a use of the compound represented by the aforementioned general formula (I) or (II), or a pharmacologically acceptable salt thereof for the manufacture of the aforementioned medicament; and a method for the preventive or therapeutic treatment of diseases in which a cytokine such as TNF, IL-1 is mediated, which comprises the step of administering a preventively or therapeutically effective amount of the compound represented by the aforementioned general formula (I) or (II), or a pharmacologically acceptable salt thereof to a mammal including a human. In addition, the present invention provides an inhibitor against production of tumor necrotizing factor (TNF) or interleukin-1 (IL-1) which comprises as an active ingredient the compound represented by the aforementioned general formula (I) or (II), or a pharmacologically acceptable salt thereof.
Specific explanations of the compounds of the aforementioned general formulas (I) and (II) of the present invention will be given below. The compounds represented by the aforementioned general formula (II) are characterized in that they have a specific saturated nitrogen-containing heterocyclic group which may have specific substituents as R3 among the compounds represented by the aforementioned general formula (I). However, the scope of the present invention is not limited to the compounds represented by the aforementioned general formula (II), and it should be understood that any compounds having as R3 a saturated nitrogen-containing heterocyclic group which may be substituted fall within the scope of the present invention.
In the aforementioned general formulas (I) and (II), examples of the alkyl group represented by R1, R2 or R4 include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group and the like.
Examples of the cycloalkyl group represented by R1 include, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and the like. Examples of the aryl group represented by R1 include, for example, phenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, pyrazinyl group, 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 5-pyrazolyl group, 2-oxazolyl group, 4-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3- isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 1,2,3-triazol-1-yl group, 1,2,3-triazol-4-yl group, 1,2,3-triazol-5-yl group, 1,2,4-triazol-1-yl group, 1,2,4-triazol-3-yl group, 1,2,4-triazol-5-yl group, 1-tetrazolyl group, 5-tetrazolyl group, 1,2,5-thiadiazol-3-yl group, 1-indolyl group, 2-indolyl group, 3-indolyl group and the like.
Examples of the halogen atom represented by R2 include, for example, fluorine atom, chlorine atom, bromine atom, and iodine atom. Examples of the amino group which may have one or two substituents that is represented by R2 include, for example, amino group, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, cyclopropylamino group , cyclobutylamino group, cyclopentylamino group, cyclohexylamino group, dimethylamino group, diethylamino group, anilino group, pyridylamino group, 4-pyridylmethylamino group, benzylamino group, p-methoxybenzylamino group, dibenzylamino group and the like. Examples of the cyclic amino group represented by R2 include, for example, 1-aziridinyl group, 1-azetidinyl group, 1-pyrrolidinyl group, piperidino group, 1-piperazinyl group, hexahydro-1H-azepin-1-yl group, hexahydro-1H-1,4-diazepin-1-yl group, morpholino group, 4-thiomorpholinyl group and the like.
Examples of the homocyclic or heterocyclic ring represented by ring A in the aforementioned general formulas (I) and (II) include, for example, benzene ring, cyclopentene ring, cyclohexene ring, cycloheptene ring, cyclooctene ring, cycloheptadiene ring, thiophene ring, furan ring, pyridine ring, pyrazine ring, pyrrole ring, thiazole ring, oxazole ring, azepine ring and the like. Examples of the alkyl group which may be substituted on the homocyclic or heterocyclic ring include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group and the like. Examples of the alkoxyl group which may be substituted on the said ring include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, neopentyloxy group, n-hexyloxy group and the like. Examples of the halogen atom which may be substituted on the said ring include, for example, fluorine atom, chlorine atom, bromine atom, and iodine atom. The number and kind of these substituents are not particularly limited, and when two or more substituents exist, they may be the same or different.
In the aforementioned general formula (I), the saturated nitrogen-containing heterocyclic group represented by R3 means a saturated nitrogen-containing heterocyclic group which has one or more nitrogen atoms as ring-constituting atom(s), and which may further have one or more oxygen atoms or sulfur atoms as ring-constituting atoms. Examples include 1-aziridinyl group, 2-aziridinyl group, 1-azetidinyl group, 2-azetidinyl group, 3-azetidinyl group, 1-pyrrolidinyl group, 2-pyrrolidinyl group, 3-pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group, piperidino group, 2-piperidyl group, 3-piperidyl group, 4-piperidyl group, 1-piperazinyl group, 2-piperazinyl group, hexahydro-1H-azepin-1-yl group, hexahydro-1H-azepin-2-yl group, hexahydro-1H-azepin-3-yl group, hexahydro-1H-azepin-4-yl group, hexahydro-1H-1,4-diazepin-1-yl group, hexahydro-1H-1,4-diazepin-2-yl group, hexahydro-1H-1,4-diazepin-5-yl group, hexahydro-1H-1,4-diazepin-6-yl group, 2-morpholinyl group, 3-morpholinyl group, morpholino group, 2-thiomorpholinyl group, 3-thiomorpholinyl group, 4-thiomorpholinyl group, 3-isoxazolidinyl group, 3-isothiazolidinyl group, 1,2,3-triazolidin-4-yl group, 1,2,4-triazolidin-3-yl group, 1,2,5-thiadiadzolin-3-yl group and the like, and preferred groups include, for example, 3-piperidyl group, 4-piperidyl group, 1-piperazinyl group, 2-piperazinyl group, 3-pyrrolidinyl group, 2-azetidinyl group, 3-azetidinyl group, 2-morpholinyl group, 2-thiomorpholinyl group and the like.
In the aforementioned general formula (II), examples of the alkanoyl group which may be substituted that is represented by R4 include, for example, formyl group, acetyl group, propionyl group, n-butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group and the like. Examples of the alkoxycarbonyl group represented by R4 include, for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, n-pentyloxycarbonyl group, n-hexyloxycarbonyl group and the like. Examples of the thiocarbamoyl group which may be substituted that is represented by R4 include, for example, thiocarbamoyl group, methylthiocarbamoyl group, ethylthiocarbamoyl group, n-propylthiocarbamoyl group, isopropylthiocarbamoyl group, n-butylthiocarbamoyl group, isobutylthiocarbamoyl group, sec-butylthiocarbamoyl group, tert-butylthiocarbamoyl group and the like. Examples of the alkanesulfonyl group represented by R4 include, for example, methanesulfonyl group, ethanesulfonyl group, n-propane sulfonyl group, n-butanesulfonyl group and the like.
In the present specification, with respect to the substituting/binding position of the terms xe2x80x9cthe aryl groupxe2x80x9d, xe2x80x9cthe homocyclic or heterocyclic ringxe2x80x9d and xe2x80x9csaturated nitrogen-containing heterocyclic groupxe2x80x9d, the terms herein used encompass any groups in their meanings which may substitute/bind at any position on a substitutable/bondable element among ring-constituting atoms, so long as the substituting/binding position is not particularly limited, as some examples are shown above.
In the aforementioned general formulas (I) and (II) of the present invention, when certain functional groups are referred to as xe2x80x9cwhich may be substitutedxe2x80x9d or xe2x80x9cwhich may have substitutents,xe2x80x9d the substituent may be any group so long as it can substitute on the functional groups. The number and kind of the substituent are not particularly limited, and when two or more substituents exist, they may be the same or different. Examples include halogen atoms such as fluorine atom, chlorine atom, and bromine atom; hydroxyl group; alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, and n-hexyl group; trifluoromethyl group; aryl groups such as phenyl group, naphthyl group, and pyridyl group; alkoxyl groups such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, and tert-butoxy group; aryloxy groups such as phenoxy group; amino groups which may be substituted such as amino group, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, cyclopropylamino group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group, dimethylamino group, diethylamino group, anilino group, pyridylamino group, benzylamino group, dibenzylamino group, acetylamino group, trifluoroacetylamino group, tert-butoxycarbonylamino group, benzyloxycarbonylamino group, benzhydrylamino group, and triphenylmethylamino group; formyl group; alkanoyl groups such as acetyl group, propionyl group, n-butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group; dichloroacetyl group, and trichloroacetyl group; alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, n-pentyloxycarbonyl group, and n-hexyloxycarbonyl group; benzyloxycarbonyl group; carbamoyl group; alkylcarbamoyl groups such as methylcarbamoyl group, ethylcarbamoyl group, n-propylcarbamoyl group, isopropylcarbamoyl group, n-butylcarbamoyl group, isobutylcarbamoyl group, sec-butylcarbamoyl group, and tert-butylcarbamoyl group; thiocarbamoyl group; alkylthiocarbamoyl groups such as methylthiocarbamoyl group, ethylthiocarbamoyl group, n-propylthiocarbamoyl group, isopropylthiocarbamoyl group, n-butylthiocarbamoyl group, isobutylthiocarbamoyl group, sec-butylthiocarbamoyl group, and tert-butylthiocarbamoyl group; amidino group; alkylthio groups such as methylthio group; alkanesulfinyl groups such as methanesulfinyl group; alkanesulfonyl groups such as methanesulfonyl group, ethanesulfonyl group, n-propanesulfonyl group, and n-butanesulfonyl group; arylsulfonyl groups such as p-toluenesulfonyl group, p-methoxybenzenesulfonyl group, and p-fluorobenzenesulfonyl group; aralkyl groups such as benzyl group, naphthyl group, pyridylmethyl group, furfuryl group, and triphenylmethyl group; nitro group; cyano group; sulfamoyl group; oxo group; hydroxyimino group; alkoxyimino groups such as methoxyimino group, ethoxyimino group, n-propoxyimino group, and isopropoxyimino group; ethylenedioxy group and the like.
The compounds represented by the aforementioned general formulas (I) and (II) of the present invention can be converted into salts, preferably, pharmacologically acceptable salts, if desired; or free bases can be generated from the resulting salts.
Examples of the salts, preferably, the pharmacologically acceptable salts, of the compounds represented by the aforementioned general formulas (I) and (II) of the present invention include acid-addition salts, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; and salts with organic acids such as acetic acid, propionic acid, butyric acid, formic acid, valeric acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, succinic acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mandelic acid, 10-camphorsulfonic acid, tartaric acid, stearic acid, gluconic acid, nicotinic acid, trifluoroacetic, acid, and benzoic acid.
Among the compounds represented by the aforementioned general formulas (I) and (II) of the present invention, optical isomers may exist for compounds having asymmetric carbons. These optical active compounds and mixtures thereof fall within the scope of the present invention.
The compounds represented by the aforementioned general formulas (I) and (II) or the salts thereof according to the present invention can exist as any crystalline form depending on manufacturing conditions, or exist as any hydrate or solvate. These crystalline forms, hydrates or solvates, and mixtures thereof fall within the scope of the present invention.
Preferred compounds of the present invention include, for example, the following compounds and salts thereof; however, the present invention is not limited to these examples:
(1) 4-chloro-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(2) 4,8-dichloro-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(3) 4-chloro-8-methyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(4) 4-chloro-8-methoxy-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(5) 4-chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(6) 4,8-dichloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(7) 4-chloro-8-methyl-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(8) 4-chloro-8-methoxy-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(9) 4-chloro-1-[2-(4-piperidyl)ethyl]-2-trifluoromethyl-1H-imidazo[4,5-c]quinoline;
(10) 4,8-dichloro-1-[2-(4-piperidyl)ethyl]-2-trifluoromethyl-1H-imidazo[4,5-c]quinoline;
(11) 4-chloro-8-methyl-1-[2-(4-piperidyl)ethyl]-2-trifluoromethyl-1H-imidazo[4,5-c]quinoline;
(12) 4-chloro-8-methoxy-1-[2-(4-piperidyl)ethyl]-2-trifluoromethyl-1H-imidazo[4,5-c]quinoline;
(13) 4-chloro-2-(4-methylphenyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(14) 4-chloro-2-(4-methoxyphenyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(15) 4-chloro-2-(4-fluorophenyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(16) 4-chloro-1-[2-(4-piperidyl)ethyl]-2-(4-trifluoromethylphenyl)-1H-imidazo[4,5-c]quinoline;
(17) 4-chloro-2-(2-furyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(18) 4-chloro-1-[2-(4-piperidyl)ethyl]-2-(2-thienyl)-1H-imidazo[4,5-c]quinoline;
(19) 4-chloro-2-(2-imidazolyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(20) 4-chloro-1-[2-(4-piperidyl)ethyl]-2-(2-thiazolyl)-1H-imidazo[4,5-c]quinoline
(21) 4-chloro-2-(5-methyl-2-thienyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(22) 4-chloro-1-[2-(4-piperidyl)ethyl]-2-(2-pyrrolyl)-1H-imidazo[4,5-c]quinoline;
(23) 4-methyl-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(24) 2-(4-fluorophenyl)-4-methyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(25) 4-methyl-1-[2-(4-piperidyl)ethyl]-2-(4-trifluoromethylphenyl)-1H-imidazo[4,5-c]quinoline;
(26) 2-(2-furyl)-4-methyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(27) 4-methyl-1-[2-(4-piperidyl)ethyl]-2-(2-thienyl)-1H-imidazo[4,5-c]quinoline;
(28) 2-(2-imidazolyl)-4-methyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(29) 4-methyl-1-[2-(4-piperidyl)ethyl]-2-(2-thiazolyl)-1H-imidazo[4,5-c]quinoline;
(30) 4-methyl-2-(3-methyl-2-thienyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(31) 4-methyl-2-(5-methyl-2-thienyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(32) 4-methyl-1-[2-(4-piperidyl)ethyl]-2-(2-pyrrolyl)-1H-imidazo[4,5-c]quinoline;
(33) 4-methyl-2-(1-methyl-2-pyrrolyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(34) 4-chloro-6,7,8,9-tetrahydro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(35) 4-chloro-6,7-dihydro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[5,4-d]cyclopenta[b]pyridine;
(36) 4-chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[5,4-d]thieno-[3,2-b]pyridine;
(37) 4-chloro-2-phenyl-1-[2-(3-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(38) 4-chloro-1-[2-(2-morpholinyl)ethyl]-2-phenyl-1H-imidazo[4,5-c]quinoline;
(39) 4-chloro-2-phenyl-1-[2-(1-piperazinyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(40) 4,6,7,8,9-pentachloro-2-ethoxymethyl-1-[2-(4-thiomorpholinyl)ethyl]-1H-imidazo[4,5-c]quinoline;
(41) 4-chloro-6,7,8,9-tetrahydro-2-hydroxymethyl-1-[2-(1-piperazinyl)ethyl]-1H-imidazo[5,4-d]cyclohepta[b]pyridine; and
(42) 4-chloro-2-(3-methyl-2-thienyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline.
The novel 1H-imidazopyridine derivatives represented by the aforementioned general formula (I) or (II) according to the present invention can be prepared by various methods; however, the preparation methods of the compounds of the present invention are not limited thereto. In the following preparation methods, specific explanations for the compounds represented by the aforementioned general formula (I) will be given, and it is obvious that these preparation methods include the compounds represented by the aforementioned general formula (II).
As the first synthetic method of the compounds of the present invention, the following synthetic method can be used in accordance with the method disclosed in Japanese Patent Unexamined Publication (KOKAI) No. Hei 3-206078/1991 or Tetrahedron, Vol. 51, p. 5813 (1995): 
wherein R5 represents hydroxyl group or an alkyl group; R6 represenmts chlorine atom or an alkyl group; R1xe2x80x2 has the same meaning as that defined for R1 (except for hydroxyl group); and R3, m and ring A have the same meanings as those defined above.
In Step 1, the compound of the general formula (IV) can be obtained by allowing the compound represented by the general formula (III) to react with a nitrating agent such as concentrated nitric acid and fuming nitric acid in the presence or absence of acetic acid, sulfuric acid or the like at a temperature ranging from 0xc2x0 C. to 200xc2x0 C.
In Step 2, the compound of the general formula (V) can be obtained by allowing the compound of the general formula (IV) to react with an appropriate chlorinating agent, for example, phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, phosphorus pentachloride or the like, in the presence or absence of a solvent such as toluene at a temperature ranging from 0xc2x0 C. to 200xc2x0 C.
In Step 3, the compound of the general formula (VII) can be obtained by reacting the amine represented by the general formula (VI) with the compound of the general formula (V) in a solvent such as N,N-dimethylformamide and toluene in the presence or absence of a base such as triethylamine and potassium carbonate at a temperature ranging from xe2x88x9210xc2x0 C. to the reflux temperature of a solvent.
In Step 4, the compound of the general formula (VIII) can be obtained by reducing the nitro group in the compound of the general formula (VII) according to an appropriate reducing method, for example, catalytic reduction using a metal catalyst such as platinum, Raney nickel, and palladium/carbon; reduction using nickel chloride and sodium borohydride; reduction using iron powder and hydrochloric acid and the like.
The reduction can be carried out in a solvent such as water, methanol, ethanol, and tetrahydrofuran, as well as a mixed solvent thereof, at a temperature ranging from 0xc2x0 C. to the reflux temperature of the solvent.
In Step 5, the compound of the general formula (IX) can be obtained by reacting the compound of the general formula (VIII) with a compound represented by the following general formula (XI), (XII) or (XIII):
wherein R represents a lower alkyl group; X represents a halogen atom; R1xe2x80x2 has the same meaning as that defined for R1 (except for hydroxyl group), in the presence or absence of a basic catalyst such as triethylamine, or an acid catalyst such as hydrochloric acid and p-toluenesulfonic acid, in the presence or absence of a solvent such as N,N-dimethylformamide, tetrahydrofuran, acetonitrile, xylene and toluene, at a temperature ranging from 0xc2x0 C. to 200xc2x0 C.
In Step 6, as a method in place of Step 5, the compound of the general formula (IX) can be obtained by reacting the compound of the general formula (VIII) with a compound represented by the following general formula (XIV):
xe2x80x83R1xe2x80x2CHOxe2x80x83xe2x80x83(XIV)
wherein R1xe2x80x2 has the same meaning as that defined for R1 (except for hydroxyl group), in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a solvent such as acetonitrile, 1,4-dioxane and tetrahydrofuran at a temperature ranging from 0xc2x0 C. to the reflux temperature of the solvent.
In Step 7, as a method in place of Step 5 or 6, the compound of the general formula (X) can be obtained by reacting the compound of the aforementioned general formula (VIII) with a compound represented by the following general formula (XV):
R1xe2x80x2COOHxe2x80x83xe2x80x83(XV)
wherein R1xe2x80x2 has the same meaning as that defined for R1 (except for hydroxyl group), in the presence or absence of an acid catalyst such as hydrochloric acid and sulfuric acid, in the presence or absence of a solvent such as N,N-dimethylformamide and toluene, at a temperature ranging from 0xc2x0 C. to 200xc2x0 C. Moreover, when R5 represents hydroxyl group in the general formula (X), the compound of the general formula (IX) can be obtained by carrying out chlorination in Step 8.
The chlorination is carried out by protecting the compound of the general formula (X), if desired, at the nitrogen atom not bound to the (CH2)m group, that is adjacent to the saturated nitrogen-containing heterocyclic group represented by R3, with a protecting group such as alkanoyl groups in a conventional manner, then reacting with an appropriate chlorinating agent, for example, phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, phosphorus pentachloride or the like in the presence or absence of a solvent such as toluene at a temperature ranging from 0xc2x0 C. to 200xc2x0 C., and further deprotecting in a conventional manner, if desired, to obtain the compound of the general formula (IX) wherein R6 is chlorine atom.
In the second synthetic method of the compounds of the present invention, the compound of the general formula (XVI): 
wherein R3, R6, m and ring A have the same meanings as those defined above, can be obtained by allowing the compound of the general formula (VIII) to react together with triphosgene in the presence of a base such as triethylamine and potassium carbonate in a solvent such as 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide and toluene at a temperature ranging from 0xc2x0 C. to the reflux temperature of a solvent.
In the third synthetic method of the compounds of the present invention, the compound of the general formula (XVII): 
wherein Z represents an aromatic ring; the symbol xe2x80x9caxe2x80x9d represents an integer of 1 or 2; and R3, R6, m and ring A have the same meanings as those defined above, can be obtained by carrying out suitable oxidation of the compound of the general formula (IX) which has an aryl group substituted with methylthio group as R1xe2x80x2, after protecting, if desired, the nitrogen atom not bound to the (CH2)m group, that is adjacent to the saturated nitrogen-containing heterocyclic group represented by R3, with a protecting group such as alkanoyl groups in a conventional manner, and further deprotecting in a conventional manner, if desired.
The oxidation can be carried out in various manners according to the desired product. More specifically, the preparation can be made, when the symbol xe2x80x9caxe2x80x9d represents an integer of 1, by reacting with an oxidizing agent, for example, chromic acid, hydrogen peroxide, m-chloroperbenzoic acid, sodium periodate, potassium periodate or the like, or when the symbol xe2x80x9caxe2x80x9d represents an integer of 2, with an oxidizing agent, for example, chromic acid, hydrogen peroxide, m-chloroperbenzoic acid, osmium tetraoxide, ruthenium tetraoxide or the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dichloroethane, methanol, acetone, and water, as well as a mixed solvent thereof, at a temperature ranging from 0xc2x0 C. to the reflux temperature of a solvent.
In the forth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R2 is hydroxyl group can be obtained by allowing a compound of the general formula (I) wherein R2 is chlorine atom to react with water and an appropriate acid or base in a solvent at a temperature ranging from 0xc2x0 C. to the reflux temperature of a solvent. Examples of the appropriate acid include, for example, organic acids such as formic acid, acetic acid, and trifluoroacetic acid, and mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid. Examples of the appropriate base include, for example, hydroxides, carbonates and hydrogencarbonates of alkali metal such as sodium and potassium and of alkaline-earth metal such as magnesium and calcium and the like. Examples of the solvent include, for example, alcohols such as methanol, ethanol and h-propanol, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran and the like, and water-containing solvents thereof.
In the fifth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R2 is fluorine atom, bromine atom or iodine atom and R1 is R1xe2x80x2 can be obtained by allowing a compound which is obtained by reacting the compound of the general formula (I) wherein R2 is chlorine atom and R1 is R1xe2x80x2 or wherein R2 is hydroxyl group and R1 is R1xe2x80x2 with trifluoromethanesulfonic anhydride, methanesulfonyl chloride or p-toluenesulfonyl chloride to react with a metal halide (e.g., potassium fluoride, sodium fluoride, lithium fluoride, potassium bromide, sodium bromide, potassium iodide, sodium iodide, etc.) in an aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide, and acetonitrile in the presence or absence of a phase-transfer catalyst such as tetraphenylphosphonium bromide, hexadecyltributylphosphonium bromide, and 18-crown-6 at a temperature ranging from 0xc2x0 C. to the reflux temperature of a solvent.
In the sixth synthetic method of the compounds of the present invention, the compound of the general formula (I), wherein R3 is a saturated nitrogen-containing heterocyclic group of which the nitrogen atom that is not bound to the adjacent (CH2)m group is deprotected, can be obtained by subjecting the compound of the general formula (I), wherein R3 is a saturated nitrogen-containing heterocyclic group having a protecting group such as alkanoyl groups, alkoxycarbonyl groups, benzyl group and trifluoromethyl group on the nitrogen atom which is not bound to the adjacent (CH2)m group, to deprotection with an acid or alkali, or to catalytic reduction with a metal catalyst, according to the type of the protecting group of the nitrogen atom.
The deprotection by using an acid or alkali can be carried out with an appropriate acid or base in the presence or absence of a cation scavenger such as anisole and thioanisole in a solvent. Examples of the solvent used include, for example, ethyl acetate, methylene chloride, 1,2-dichloroethane, 1,4-dioxane, methanol, ethanol, n-propanol, N,N-dimethylformamide, tetrahydrofuran, and water, as well as a mixed solvent thereof. Examples of the acid used include, for example, hydrochloric acid, an ethyl acetate solution of hydrogen chloride, an ethanolic solution of hydrogen chloride, sulfuric acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid and the like. Examples of the base include, for example, hydroxides, carbonates and hydrogencarbonates of alkali metal such as sodium and potassium, and of alkaline-earth metal such as magnesium and calcium and the like. The reaction can be carried out at a temperature ranging from 0xc2x0 C. to the reflux temperature of a solvent.
The catalytic reduction can be carried out by using an appropriate metal catalyst such as platinum, palladium/carbon, Raney nickel, Pearlman""s reagent in water, an alcohol such as methanol, ethanol and n-propanol, and acetic acid, as well as a mixed solvent thereof in the presence or absence of an acid such as hydrochloric acid at a temperature ranging from room temperature to the reflux temperature of the solvent under a pressure ranging from normal pressure to 200 kg/cm2.
In the seventh synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R2 is phenoxy group which may be substituted can be obtained by reacting the compound of the general formula (I) wherein R2 is chlorine atom with a phenol derivative which may be substituted in the presence of a base such as sodium hydroxide and potassium hydroxide in the presence or absence of a solvent such as N,N-dimethylformamide and toluene at a temperature ranging from 0xc2x0 C. to 200xc2x0 C.
In the eighth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R2 is amino group can be obtained by subjecting the compound of the general formula (I) wherein R2 is phenoxy group which may be substituted, that is obtained by the seventh synthetic method, to reaction together with ammonium acetate in the presence or absence of a solvent such as N,N-dimethylformamide and toluene at a temperature ranging from 0xc2x0 C. to 200xc2x0 C.
In the ninth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R2 is amino group which may have one or two substituents or a cyclic amino group which may be substituted can be obtained by subjecting the compound of the general formula (I) wherein R2 is chlorine atom to reaction together with an amine derivative which may have one or two substituents or a cyclic amine derivative which may be substituted in the presence or absence of a base such as triethylamine, potassium carbonate and sodium hydride in the presence or absence of a solvent such as water, alcohols including methanol, ethanol and n-propanol, methylene chloride, 1,2-dichlroethane, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran and toluene at a temperature ranging from 0xc2x0 C. to 200xc2x0 C. under normal pressure or a pressurized condition.
In the tenth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R2 is amino group can be obtained by subjecting the compound of the general formula (I) wherein R2 is bentzylamino group, dibenzylamino group, or p-methoxybenzylamino group, which is obtained in the ninth synthetic method, to catalytic reduction by using an appropriate metal catalyst, or by subjecting the compound of the general formula (I) wherein R2 is p-methoxybenzylamino group to deprotection using an acid.
The catalytic reduction can be carried out with a metal catalyst such as palladium/carbon and Pearlman""s reagent in a solvent such as alcohols including methanol and ethanol, and water, as well as a mixed solvent thereof at a temperature ranging from room temperature to the reflux temperature of a solvent in the presence or absence of an acid such as hydrochloric acid, acetic acid and formic acid, ammonium formate, cyclohexene, and cyclohexadiene under a pressure ranging from normal pressure to 200 kg/cm2. The deprotection using an acid can be carried out with an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid and trifluoromethanesulfonic acid in a solvent such as alcohols including methanol and ethanol, methylene chloride, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, toluene, and N,N-dimethylformamide in the presence or absence of a cation scavenger such as anisole and thioanisole at a temperature ranging from 0xc2x0 C. to the reflux temperature of a solvent.
In the eleventh synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R3 is a saturated nitrogen-containing heterocyclic group which is substituted with oxo group can be obtained by reacting the compound of the general formula (I) wherein R3 is a saturated nitrogen-containing heterocyclic group which is substituted with ethylenedioxy group, with an acid such as hydrochloric acid, an ethyl acetate solution of hydrogen chloride, an ethanolic solution of hydrogen chloride, sulfuric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, formic acid and acetic acid in the presence or absence of a solvent such as ethyl acetate, methylene chloride, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, n-propanol and N,N-dimethylformamide, or a water-containing solvent thereof at a temperature ranging from 0xc2x0 C. to 200xc2x0 C.
In the twelfth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R3 is a saturated nitrogen-containing heterocyclic group which is substituted with hydroxyimino group or an alkoxyimino group can be obtained by reacting the compound of the general formula (I) wherein R3 is a saturated nitrogen-containing heterocyclic group which is substituted with oxo group, that is obtained by the eleventh synthetic method, with a compound represented by the following general formula (XVIII):
R7xe2x80x94Oxe2x80x94NH2xe2x80x83xe2x80x83(XVIII)
wherein R7 represents hydrogen atom or an alkyl group, in the presence or absence of a base such as triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and sodium acetate in a solvent such as alcohols including methanol, ethanol and n-propanol, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and toluene at a temperature ranging from 0xc2x0 C. to the reflux temperature of a solvent.
In the thirteenth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R2 is hydrogen atom can be obtained by subjecting the compound of the general formula (I) wherein R2 is chlorine atom to catalytic reduction using a metal catalyst such as platinum and palladium/carbon in the presence or absence of an acid such as hydrochloric acid and acetic acid in an alcohol solvent such as methanol and ethanol or a water-containing solvent thereof under normal pressure at a temperature ranging from room temperature to the reflux temperature of a solvent.
In the fourteenth synthetic method of the compounds of the present invention, the compound of the general formula (I), wherein R3 is a saturated nitrogen-containing heterocyclic group having an appropriate substituent on the nitrogen atom which is not bound to the adjacent (CH2)m group, can be obtained by reacting an appropriate reagent with the compound of the general formula (I) wherein R3 is a saturated nitrogen-containing heterocyclic group not having a protecting group on the nitrogen atom which is not bound to the adjacent (CH2)m group.
The reaction can be carried out in the presence or absence of a solvent such as N,N-dimethylformamide, methylene chloride, tetrahydrofuran, toluene, pyridine, nitrobenzene, 1,2-dichloroethane, 1,4-dioxane, methanol, ethanol, n-propanol and water, as well as a mixed solvent thereof, in the presence or absence of a base such as triethylamine and potassium carbonate at a temperature ranging from 0xc2x0 C. to 200xc2x0 C.
Examples of the appropriate reagent include, for example, alkyl halides, triphenylmethyl chloride, benzyl chloride, benzhydryl chloride, a mixture of formic acid and formalin, acetyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoyl chloride, benzyl chlorocarbonate, ethyl chlorocarbonate, di-tert-butyl dicarbonate, sodium cyanate, alkyl isocyanates, sodium thiocyanate, alkyl isothiocyanates, 1H-pyrazole-1-carboxamidine, methanesulfonyl chloride, p-toluenesulfonyl chloride, p-fluorobenzenesulfonyl chloride, urethanes, alkylurethanes, thiourethanes, alkylthiourethanes and the like.
In the fifteenth synthetic method of the compounds of the present invention, the compound of the general formula (I), wherein R3 is a saturated nitrogen-containing heterocyclic group substituted with an alkoxycarbonyl group or benzyloxycarbonyl group on the nitrogen atom which is not bound to the adjacent (CH2)m group, can be obtained by reacting the compound of the general formula (I) wherein R3 is a saturated nitrogen-containing heterocyclic group substituted with an alkyl group or benzyl group on the nitrogen atom which is not bound to the adjacent (CH2)m group with an alkyl chlorocarbonate or benzyl chlorocarbonate in the presence or absence of a solvent such as methylene chloride and toluene in the presence or absence of a base such as triethylamine and potassium carbonate at a temperature ranging from 0xc2x0 C. to 200xc2x0 C.
Some of the compounds represented by the general formulas (III) to (VIII) which are starting materials or synthetic intermediates in the preparations of the compounds of the present invention are known compounds, which are disclosed in, for example, Journal of Medicinal Chemistry, Vol. 18, p. 726 (1975); Vol. 33, p. 1880 (1990); and Vol. 40, p. 1779 (1997); International Patent Publication No. 97/20820; European Patent Publication No. 223124 (1987) and the like, and can be prepared according to the method described therein. The preparations of some novel compounds will be described in reference examples.
The medicaments which comprise as an active ingredient the novel 1H-imidazopyridine derivative represented by the aforementioned general formula (I) or (II) or a salt thereof are generally administered as oral preparations in the forms of capsules, tablets, fine granules, granules, powders, syrups, dry syrups and the like, or as parenteral preparations in the forms of injections, suppositories, eye drops, eye ointments, ear drops, nasal drops, dermal preparations, inhalations and the like. These formulations can be manufactured according to conventional methods by addition of pharmacologically and pharmaceutically acceptable additives. For example, in the oral preparations and suppositories, pharmaceutical ingredients may be used such as excipients such as lactose, D-mannitol, corn starch, and crystalline cellulose; disintegrators such as carboxymethylcellulose and carboxymethylcellulose calcium; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone; lubricants such as magnesium stearate and talc; coating agents such as hydroxypropylmethylcellulose, sucrose, and titanium oxide; bases such as polyethylene glycol and hard fat and the like. In injections, or eye or ear drops and the like, pharmaceutical ingredients may be used such as solubilizers or solubilizing aids which may constitute aqueous preparations or those dissolved upon use such as distilled water for injection, physiological saline, and propylene glycol; pH modifiers such as inorganic or organic acids or bases; isotonicities such as sodium chloride, glucose, and glycerin; stabilizers and the like; and in eye ointments and dermal preparations, pharmaceutical ingredients which are suitable for ointments, creams and patches such as white vaseline, macrogols, glycerin, and cotton cloth.
A dose of the compounds of the present invention to a patient under therapeutic treatment is generally from about 0.1 to 1,000 mg in oral administration, and from about 0.01 to 500 mg in parenteral administration for an adult, which may depend on the symptoms of the patient. The aforementioned dose can be administered once a day or several times a day as divided portions. However, it is desirable that the aforementioned dose may suitably be increased or decreased according to a purpose of a therapeutic or preventive treatment, part or type of a disease, and the age or symptoms of a patient.